In the USA, prostate cancer (PC) is the second leading cause of cancer-related death in men; aging is a major risk factor and African Americans (AA) are at a higher risk than white Americans (WA). The American Cancer Society estimates that 1 in 9,879 (0-39 year-old), 1 in 39 (40-59 year-old), and 1 in 7 (60-79 year-old) will be diagnosed with invasive PC. Older people develop trace element deficiencies (e.g., selenium); recently, we showed that older rats also develop selenium deficiency. Selenium deficiency increases the risk of oxidative stress and cancer. Selenium-enriched yeast (SY) supplementation has been shown to protect against prostate cancer in humans; however, the dose and the form of selenium as a function of age, as well as the mechanism of action, remain to be elucidated. In a pilot study, we showed that SY (240 5g/day for 9 months) inhibits oxidative stress, reduces PSA levels in healthy men <40 years of age. We report for the first time that SY also inhibited 1-1 antitrypsin (ATT); this protein has been reported to be over expressed in PC patients and its levels are positively correlated with PSA levels and are higher in AA than WA. Our hypothesis is that selenium dose must be tailored as a function of age to be effective in inhibiting oxidative stress and other markers of risk in different age groups and such inhibition is, in part, due to selenium interaction with redox-sensitive proteins including ATT that may be involved in cell proliferation and/or apoptosis. To test our hypothesis, we will conduct a double-blind, randomized, placebo-controlled clinical trial of selenium supplementation in the form of selenomethionine (SM=200 5g/day) and SY (240 5g/day and 350 5g/day the higher dose will deliver 200 5g/day of SM; (the variability of SM in SY [SelenoExcell, Cypress Co., Fresno, CA] is less than 3%) for 9 months to healthy AA and WA men in various age groups (25 men/group): Young (20-39 year old), Matured (40-59 year old), and Old (60-79 year old) adults. SM is currently being used in a major clinical trial in the USA (SELECT) and SY is employed in the trial in Europe (PRECISE); the results will be known in 2013 and beyond. Specifically, we will determine the effect of selenium supplementation on: 1. plasma (compliance) and urinary (bioavailability) selenium levels and form, 2. biomarkers of risk PSA levels and testosterone metabolism, 3. biomarkers of oxidative stress blood glutathione (GSH) and protein bound GSH (bGSH), urinary 8-hydroxy- 22-deoxyguanosine levels, urinary and plasma F2-isoprostane levels, and plasma 3-nitrotyrosine levels, and 4. plasma proteomic profiles of redox-sensitive proteins (e.g., ATT). The results will provide insights into the form and dose that may contribute to the protective effect of selenium as a function of age. This study involves both basic scientists, a urologist and a clinical oncologist in the area of PC and the results will provide novel biomarkers that can be used in the current and future selenium intervention trials. PUBLIC HEALTH RELEVANCE: In the USA, prostate cancer (PC) is the second leading cause of cancer-related death in men; aging is a major risk factor and African Americans are at a higher risk than white Americans. Selenium has been shown to protect against PC in humans; however, the dose and the form of selenium as a function of age, as well as the mechanism of action, remain to be elucidated. The results of these studies are vital for the further development and appropriate tailoring of selenium agents (form and dose) as a function of age for the purpose of a more effective chemoprevention program. Furthermore, this study will provide novel biomarkers that can be used for early detection of this disease and in the major clinical selenium intervention trials that are currently being conducted in the world, including SELECT in the USA. Collectively, studies proposed here are essential to the control and prevention of PC in men.